Summary Myeloid-derived suppressor cells (MDSCs) are crucial drivers of chronic inflammation and potent suppressors of immune responses. Aberrant expansion and dysregulated functions of MDSCs contribute to the pathogenesis of numerous human diseases involving chronic inflammation. MDSCs are recognized as an important therapeutic target for these diseases, and Intensive efforts are currently directed at developing therapies to inhibit the expansion of MDSCs and to block the functions of MDSCs. Identification of new regulators of MDSCs is thus critical for the development of such novel therapies. This exploratory proposal aims to elucidate the roles and signaling mechanisms of a novel emerging regulator of MDSCs, TRAF3, a signal transducer of a variety of immune receptors. By examining a new mouse model that has TRAF3 specifically deleted in myeloid cells (M-TRAF3-/- mice), we recently found that TRAF3 inhibits chronic inflammation and infection likely through controlling the expansion of MDSCs. In strong corroboration of our findings, increasing evidence indicates that a number of TRAF3-employing immune receptors directly regulate the expansion and/or suppressive activities of MDSCs. Despite its likely importance, the direct roles of TRAF3 in MDSCs remain unknown. We will address this significant gap in knowledge in the current proposal. Based on our new findings and preliminary results, we will test the central hypothesis that TRAF3 and TRAF3-dependent signaling pathways directly control the expansion and suppressive functions of MDSCs, thereby inhibiting chronic inflammation. To address this, we propose complementary in vitro and in vivo studies to decipher the cellular and molecular mechanisms underlying TRAF3-mediated regulation of MDSCs. Importantly, we will identify the intrinsic signaling pathways of immune receptor(s) that play dominant roles in the TRAF3-dependent processes in MDSCs. Our long-term goal is to gain new insights into the regulatory mechanisms of MDSC physiology as well as MDSC-mediated chronic inflammation and immunosuppression in disease pathogenesis. Such knowledge will pave the way towards developing innovative therapeutic strategies to manipulate TRAF3 signaling pathways in MDSCs for the treatment of chronic inflammatory diseases, cancers, autoimmune diseases, and chronic infectious diseases.